Molecular Interaction Between the Microenvironment and FLT3/ITD+ AML Cells Leading to the Refractory Phenotype

Internal tandem duplication mutations in the FLT3 gene (FLT3/ITD) are detected in 10–15% of children and 30% of adult patients with AML and are associated with an extremely poor prognosis. Although several antagonists against FLT3/ITD have been developed, few of them are effective for the treatment of FLT3/ITD+ AML because of the emergence of drug-resistant cells. The mechanisms responsible for drug resistance include the acquisition of additional mutations in the FLT3 gene and/or activation of other prosurvival pathways such as microenvironment-mediated resistance. Recent studies have strongly suggested that the reciprocal interaction between the microenvironment and AML cells generates specific machinery that leads to chemoresistance. This chapter describes the molecular mechanism responsible for the refractory phenotype of FLT3/ITD+ AML cells resulting from the communication between the microenvironment and FLT3/ITD+ leukemia cells. Understanding this mechanism enables the discovery of novel and innovative therapeutic interventions for resistant FLT3/ITD+ AML

The Dynamical State of the Serpens South Filamentary Infrared Dark Cloud

We present the results of N_2H^+ (J = 1-0) observations toward Serpens South, the nearest cluster-forming, infrared dark cloud. The physical quantities are derived by fitting the hyperfine structure of N_2H^+. The Herschel and 1.1 mm continuum maps show that a parsec-scale filament fragments into three clumps with radii of 0.1-0.2 pc and masses of 40-230 M_☉. We find that the clumps contain smaller-scale (~0.04 pc) structures, i.e., dense cores. We identify 70 cores by applying CLUMPFIND to the N_2H^+ data cube. In the central cluster-forming clump, the excitation temperature and line-width tend to be large, presumably due to protostellar outflow feedback and stellar radiation. However, for all the clumps, the virial ratios are evaluated to be 0.1-0.3, indicating that the internal motions play only a minor role in the clump support. The clumps exhibit no free fall but exhibit low-velocity infall, and thus the clumps should be supported by additional forces. The most promising force is the globally ordered magnetic field observed toward this region. We propose that the Serpens South filament was close to magnetically critical and ambipolar diffusion triggered the cluster formation. We find that the northern clump, which shows no active star formation, has a mass and radius comparable to the central cluster-forming clump and is therefore a likely candidate of a pre-protocluster clump. The initial condition for cluster formation is likely to be a magnetically supported clump of cold, quiescent gas. This appears to contradict the accretion-driven turbulence scenario, for which the turbulence in the clumps is maintained by the accretion flow

Internal Tandem Duplication in FLT3 Attenuates Proliferation and Regulates Resistance to the FLT3 Inhibitor AC220 by Modulating p21Cdkn1a and Pbx1 in Hematopoietic Cells

Internal tandem duplication (ITD) mutations in the Fms-related tyrosine kinase 3 (FLT3) gene (FLT3-ITD) are associated with poor prognosis in patients with acute myeloid leukemia (AML). Due to the development of drug resistance, few FLT3-ITD inhibitors are effective against FLT3-ITD+ AML. In this study, we show that FLT3-ITD activates a novel pathway involving p21Cdkn1a (p21) and pre-B cell leukemia transcription factor 1 (Pbx1) that attenuates FLT3-ITD cell proliferation and is involved in the development of drug resistance. FLT3-ITD up-regulated p21 expression in both mouse bone marrow c-kit+-Sca-1+-Lin- (KSL) cells and Ba/F3 cells. The loss of p21 expression enhanced growth factor-independent proliferation and sensitivity to cytarabine as a consequence of concomitantly enriching the S+G2/M phase population and significantly increasing the expression of Pbx1, but not Evi-1, in FLT3-ITD+ cells. This enhanced cell proliferation following the loss of p21 was partially abrogated when Pbx1 expression was silenced in FLT3-ITD+ primary bone marrow colony-forming cells and Ba/F3 cells. When FLT3-ITD was antagonized with AC220, a selective inhibitor of FLT3-ITD, p21 expression was decreased coincident with Pbx1 mRNA up-regulation and a rapid decline in the number of viable FLT3-ITD+ Ba/F3 cells; however, the cells eventually became refractory to AC220. Overexpressing p21 in FLT3-ITD+ Ba/F3 cells delayed the emergence of cells that were refractory to AC220, whereas p21 silencing accelerated their development. These data indicate that FLT3-ITD is capable of inhibiting FLT3-ITD+ cell proliferation through the p21/Pbx1 axis and that treatments that antagonize FLT3-ITD contribute to the subsequent development of cells that are refractory to a FLT3-ITD inhibitor by disrupting p21 expression

Variantes genéticas en el locus 9p21 contribuyen al desarrollo de arteriosclerosis a través de la modulación de ANRIL y CDKN2A/B

Registro creado en correspondencia al grado de doctora de Ada Congrains Castillo.Los estudios de asociación de todo el genoma (GWAS) han identificado variantes genéticas que contribuyen al riesgo de enfermedad cardiovascular (ECV) en el locus del cromosoma 9p21. La región asociada a CVD es adyacente a los dos inhibidores de quinasas dependientes de ciclina (CDKN) 2A y 2B y los últimos exones del ARN no codificante, ANRIL. Todavía no está claro cuál de estas transcripciones o cómo están involucradas en la patogénesis de la aterosclerosis.Genome-wide association studies (GWAS) have identified genetic variants contributing to the risk of cardiovascular disease (CVD) at the chromosome 9p21 locus. The CVD-associated region is adjacent to the two cyclin dependent kinase inhibitors (CDKN)2A and 2B and the last exons of the non-coding RNA, ANRIL. It is still not clear which of or how these transcripts are involved in the pathogenesis of atherosclerosis.Japón. Programa de Promoción de Estudios Fundamentales en el Instituto Nacional de Innovación Biomédica de Japón (HR: 22-2-5), el Ministerio de Educación, Cultura, Deportes, Ciencia y Tecnología de Japón (KK: 22510211) y la Fundación NOVARTIS para la Investigación Gerontológica (KK).Tesi

広域教育網構築に向けた2つの双方向衛星通信システムの接続

現在、日本国内で通信衛星を利用した双方向型(多地点型)画像・音声会議システムとしては、主に大学や国立教育研究機関を相互に結ぶSpace Collaboration System (SCS)と、国立大学医学部附属病院間を結ぶMedical Information Network by Communication Satellite for University Hospitals (MINCS-UH、愛称MINCS)が並存している。2システムを融合すれば、地上局数は180となり、全国の国立大学のほとんどをカバーでき、医療者の効率のよい再教育体制が構築できると共に、学際的研究をより発展させることが期待される。そこで、両システムを接続して双方向型の番組放映が可能であるか確認した。試験には、SCS地上固定局が3局、MINCSは講義校1局と質問校2局が参加した。その結果、システム間相互に信号をやり取りする部分でいくつかの不具合が発生したが、最終的には双方向での音声・画像による模擬的会議に成功した。これにより、両システムを接続して全国180の地上局を有する大規模衛星講義(会議)システムの有効性を確認できた。既存のシステムを活用し、さらに大規模な双方向型の通信システムを構築することは、教育機会の均等化、地域格差の是正、さらには災害対策としても有効であると考えられる。In Japan, two systems for two-way (multi-point) audiovisual satellite communication are currently in connecting mainly universities and national educational research organizations, and the "Medical Information Network by Communication Satellite for University Hospitals" (MINCS), which connects 30 of the 42 National University Hospitals. If these systems were connected, the number of earth stations would exceed 180, connecting most National Universities. This would facilitate the development of efficient ongoing education programs for the medical staff and allow the development of interdisciplinary study. Therefore, we attempted to connect the two systems in order to examine the possibility of two-way programming. Three MINCS earth stations and three SCS earth stations took part in the experiment. Teleconference in both directions was successful despite of some problems with signal exchange. The use of existing systems along with construction of a largerscale multi-point communication system would be useful in equalizing educational opportunities by correction of regional gaps. This system also has potential as a communication medium for use in disasters

What is the quantity of consumer goods stocked in a Japanese household? Estimating potential disaster waste generation during floods

This study aims to estimate micro material stock derived from consumer goods m fundamental data such as possession and expenditure of consumer goods in housing, considering the type of housing and class of total floor area of housing. A questionnaire survey of residents living in the eight cities of the Tama river basin was conducted to clarify the possession and expenditure of consumer goods in units of items/housing and JPY/housing. Identified consumer goods were 14 types and 97 items. The questionnaire also asked the storeys on which the consumer goods are installed. Material intensity coefficients (MIC) regarding the weight of consumer goods were calculated based on web‒based and statistical surveys in units of kg/item and kg/USD. Micro material stock derived from consumer goods in housing totalled 5.84 tonnes (t) in detached housing and 5.71 t in complex housing. Amount of the micro material stock derived from consumer goods corresponds to 10.9% of the macro material stock derived from detached housing. Reliability and validity of questionnaire results and the MIC were confirmed through two types of sensitivity analysis. As a case study, the total weight of all consumer goods in Kawasaki City was calculated as 3,667,000 t. The disaster waste derived from consumer goods considering the flood damage was estimated based on the total weight of all consumer goods in the city. The resulting estimation was 229,000 t. This estimation is 0.72 times bigger than the above-mentioned result that considered the storeys on which the consumer goods are installed